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New insights into the genetic basis of premature ovarian insufficiency: novel causative variants and candidate genes revealed by genomic sequencing

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Item embargoed until 2021-06-19. Restrictions imposed by the publisher
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Date
2020
Author(s)
Jaillard, Sylvie
Bell, Katrina
Akloul, Linda
Walton, Kelly
McElreavy, Kenneth
Stocker, William A
Beaumont, Marion
Harrisson, Craig
Jääskeläinen, Tiina
Palvimo, Jorma J
Robevska, Gorjana
Launay, Erika
Satié, Anne-Pascale
Listyasari, Nurin
Bendavid, Claude
Sreenivasan, Rajini
Duros, Solène
van den Bergen, Jocelyn, Henry, Catherine
Domin-Bernhard, Mathilde
et al.
Unique identifier
10.1016/j.maturitas.2020.06.004
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Citation
Jaillard, Sylvie. Bell, Katrina. Akloul, Linda. Walton, Kelly. McElreavy, Kenneth. Stocker, William A. Beaumont, Marion. Harrisson, Craig. Jääskeläinen, Tiina. Palvimo, Jorma J. Robevska, Gorjana. Launay, Erika. Satié, Anne-Pascale. Listyasari, Nurin. Bendavid, Claude. Sreenivasan, Rajini. Duros, Solène. van den Bergen, Jocelyn, Henry, Catherine. Domin-Bernhard, Mathilde. et al.. (2020). New insights into the genetic basis of premature ovarian insufficiency: novel causative variants and candidate genes revealed by genomic sequencing.  Maturitas, 141, 9-19. 10.1016/j.maturitas.2020.06.004.
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© 2020 Elsevier B.V.
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CC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
Abstract

Ovarian deficiency, including premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR), represents one of the main causes of female infertility. POI is a genetically heterogeneous condition but current understanding of its genetic basis is far from complete, with the cause remaining unknown in the majority of patients. The genes that regulate DOR have been reported but the genetic basis of DOR has not been explored in depth. Both conditions are likely to lie along a continuum of degrees of decrease in ovarian reserve. We performed genomic analysis via whole exome sequencing (WES) followed by in silico analyses and functional experiments to investigate the genetic cause of ovarian deficiency in ten affected women. We achieved diagnoses for three of them, including the identification of novel variants in STAG3, GDF9, and FANCM. We identified potentially causative FSHR variants in another patient. This is the second report of biallelic GDF9 and FANCM variants, and, combined with functional support, validates these genes as bone fide autosomal recessive “POI genes”. We also identified new candidate genes, NRIP1, XPO1, and MACF1. These genes have been linked to ovarian function in mouse, pig, and zebrafish respectively, but never in humans. In the case of NRIP1, we provide functional support for the deleterious nature of the variant via SUMOylation and luciferase/β-galactosidase reporter assays. Our study provides multiple insights into the genetic basis of POI/DOR. We have further elucidated the involvement of GDF9, FANCM, STAG3 and FSHR in POI pathogenesis, and propose new candidate genes, NRIP1, XPO1, and MACF1, which should be the focus of future studies.

Subjects
premature ovarian insufficiency   female infertility   genomics   
URI
https://erepo.uef.fi/handle/123456789/8312
Link to the original item
http://dx.doi.org/10.1016/j.maturitas.2020.06.004
Publisher
Elsevier BV
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  • Terveystieteiden tiedekunta [1336]
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